Regulation of blood flow and volume exchange across the microcirculation

Oxygen delivery to cells is the basic prerequisite of life. Within the human body, an ingenious oxygen delivery system, comprising steps of convection and diffusion from the upper airways via the lungs and the cardiovascular system to the microvascular area, bridges the gap between oxygen in the outside airspace and the interstitial space around the cells. However, the complexity of this evolutionary development makes us prone to pathophysiological problems. While those problems related to respiration and macrohemodynamics have already been successfully addressed by modern medicine, the pathophysiology of the microcirculation is still often a closed book in daily practice. Nevertheless, here as well, profound physiological understanding is the only key to rational therapeutic decisions. The prime guarantor of tissue oxygenation is tissue blood flow. Therefore, on the premise of intact macrohemodynamics, the microcirculation has three major responsibilities: 1) providing access for oxygenated blood to the tissues and appropriate return of volume;2) maintaining global tissue flood flow, even in the face of changes in central blood pressure;and 3) linking local blood flow to local metabolic needs. It is an intriguing concept of nature to do this mainly by local regulatory mechanisms, impacting primarily on flow resistance, be this via endothelial or direct smooth muscle actions. The final goal of microvascular blood flow per unit of time is to ensure the needed exchange of substances between tissue and blood compartments. The two principle means of accomplishing this are diffusion and filtration. While simple diffusion is the quantitatively most important form of capillary exchange activity for the respiratory gases, water flux across the blood-brain barrier is facilitated via preformed specialized channels, the aquaporines. Beyond that, the vascular barrier is practically nowhere completely tight for water, with paracellular filtration giving rise to generally low but permanent fluid flux outwards into the interstitial space at the microvascular high pressure segment. At the more leaky venular aspect, both filtration and diffusion allow for bidirectional passage of water, nutrients, and waste products. We are just beginning to appreciate that a major factor for maintaining tissue fluid homeostasis appears to be the integrity of the endothelial glycocalyx

Heparinase selectively sheds heparan sulphate from the endothelial glycocalyx

A healthy vascular endothelium is coated by the endothelial glycocalyx. Its main constituents are transmembrane syndecans and bound heparan sulphates. This structure maintains the physiological endothelial permeability barrier and prevents leukocyte and platelet adhesion, thereby mitigating inflammation and tissue oedema. Heparinase, a bacteria] analogue to heparanase, is known to attack the glycocalyx. However, the exact extent and specificity of degradation is unresolved. We show by electron microscopy, immunohistological staining and quantitative measurements of the constituent parts, that heparinase selectively sheds heparan sulphate from the glycocalyx, but not the synclecans

Perspectives in Microvascular Fluid Handling: Does the Distribution of Coagulation Factors in Human Myocardium Comply with Plasma Extravasation in Venular Coronary Segments?

Background: Heterogeneity of vascular permeability has been suggested for the coronary system. Whereas arteriolar and capillary segments are tight, plasma proteins pass readily into the interstitial space at venular sites. Fittingly, lymphatic fluid is able to coagulate. However, heart tissue contains high concentrations of tissue factor, presumably enabling bleeding to be stopped immediately in this vital organ. The distribution of pro- and anti-coagulatively active factors in human heart tissue has now been determined in relation to the types of microvessels. Methods and Results: Samples of healthy explanted hearts and dilated cardiomyopathic hearts were immunohistochemically stained. Albumin was found throughout the interstitial space. Tissue factor was packed tightly around arterioles and capillaries, whereas the tissue surrounding venules and small veins was practically free of this starter of coagulation. Thrombomodulin was present at the luminal surface of all vessel segments and especially at venular endothelial cell junctions. Its product, the anticoagulant protein C, appeared only at discrete extravascular sites, mainly next to capillaries. These distribution patterns were basically identical in the healthy and diseased hearts, suggesting a general principle. Conclusions: Venular extravasation of plasma proteins probably would not bring prothrombin into intimate contact with tissue factor, avoiding interstitial coagulation in the absence of injury. Generation of activated protein C via thrombomodulin is favored in the vicinity of venular gaps, should thrombin occur inside coronary vessels. This regionalization of distribution supports the proposed physiological heterogeneity of the vascular barrier and complies with the passage of plasma proteins into the lymphatic system of the heart. Copyright (C) 2010 S. Karger AG, Base

Small-volume resuscitation with hyperoncotic albumin: a systematic review of randomized clinical trials

Background Small-volume resuscitation can rapidly correct hypovolemia. Hyperoncotic albumin solutions, long in clinical use, are suitable for small-volume resuscitation; however, their clinical benefits remain uncertain. Methods Randomized clinical trials comparing hyperoncotic albumin with a control regimen for volume expansion were sought by multiple methods, including computer searches of bibliographic databases, perusal of reference lists, and manual searching. Major findings were qualitatively summarized. In addition, a quantitative meta-analysis was performed on available survival data. Results In all, 25 randomized clinical trials with a total of 1,485 patients were included. In surgery, hyperoncotic albumin preserved renal function and reduced intestinal edema compared with control fluids. In trauma and sepsis, cardiac index and oxygenation were higher after administration of hydroxyethyl starch than hyperoncotic albumin. Improved treatment response and renal function, shorter hospital stay and lower costs of care were reported in patients with liver disease receiving hyperoncotic albumin. Edema and morbidity were decreased in high-risk neonates after hyperoncotic albumin administration. Disability was reduced by therapy with hyperoncotic albumin in brain injury. There was no evidence of deleterious effects attributable to hyperoncotic albumin. Survival was unaffected by hyperoncotic albumin (pooled relative risk, 0.95; 95% confidence interval 0.78 to 1.17). Conclusion In some clinical indications, randomized trial evidence has suggested certain benefits of hyperoncotic albumin such as reductions in morbidity, renal impairment and edema. However, further clinical trials are needed, particularly in surgery, trauma and sepsis

Exogenous nitric oxide requires an endothelial glycocalyx to prevent postischemic coronary vascular leak in guinea pig hearts

Introduction Postischemic injury to the coronary vascular endothelium, in particular to the endothelial glycocalyx, may provoke fluid extravasation. Shedding of the glycocalyx is triggered by redox stress encountered during reperfusion and should be alleviated by the radical scavenger nitric oxide (NO). The objective of this study was to investigate the effect of exogenous administration of NO during reperfusion on both coronary endothelial glycocalyx and vascular integrity. Methods Isolated guinea pig hearts were subjected to 15 minutes of warm global ischemia followed by 20 minutes of reperfusion in the absence (Control group) and presence (NO group) of 4 mu M NO. In further experiments, the endothelial glycocalyx was enzymatically degraded by means of heparinase followed by reperfusion without (HEP group) and with NO (HEP+NO group). Results Ischemia and reperfusion severely damaged the endothelial glycocalyx. Shedding of heparan sulfate and damage assessed by electron microscopy were less in the presence of NO. Compared with baseline, coronary fluid extravasation increased after ischemia in the Control, HEP, and HEP+NO groups but remained almost unchanged in the NO group. Tissue edema was significantly attenuated in this group. Coronary vascular resistance rose by 25% to 30% during reperfusion, but not when NO was applied, irrespective of the state of the glycocalyx. Acute postischemic myocardial release of lactate was comparable in the four groups, whereas release of adenine nucleotide catabolites was reduced 42% by NO. The coronary venous level of uric acid, a potent antioxidant and scavenger of peroxynitrite, paradoxically decreased during postischemic infusion of NO. Conclusion The cardioprotective effect of NO in postischemic reperfusion includes prevention of coronary vascular leak and interstitial edema and a tendency to forestall both no-reflow and degradation of the endothelial glycocalyx

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO